The overall goal of this project is to elucidate interacting endogenous anti-inflammatory pathways that can be harnessed to suppress an over-exuberant host response to periodontal bacteria and other pathogens. Bacteria are initially recognized by Toll-like receptors (TLRs) and other pathogen recognition receptors expressed on innate cells. TLR interaction with microbe-specific molecular patterns induces the innate production of pro- inflammatory cytokines, which direct the intensity and direction of the immune response, leads to recruitment of leukocytes to the site of infection, and the production of an arsenal of anti-bacterial molecules, many of which have the potential to cause the collateral tissue damage that defines destructive inflammatory diseases. There are at least three endogenous anti-inflammatory pathways. The first life cycle of DE017680 focused on the in vitro elucidation of the PI3K/ AKT anti-inflammatory pathway, the key role of GSK3b in this signaling cascade, and the mechanisms by which this pathway regulates the expression of IFNb, IL-1Ra, IL-10 in innate cells in addition to controlling T cell development and proliferation. In addition o the PI3K/ AKT cascade, this renewal will also consider the a7 nicotinic acetylcholine receptor-dependent cholinergic and the Wnt3a anti- inflammatory pathways. Crosstalk between these three pathways will be elucidated, with particular attention paid to the pivotal role of the centra inflammatory mediator, GSK3b, in pathway convergence. While each pathway is efficacious in its own right, therapeutic interventions that maximize the anti-inflammatory potential of convergent signaling events are likely to be particularly potent. To this end, anti-inflammatory signaling events will be exploited using murine models of inflammation (sub-cutaneous chamber) and periodontitis (alveolar bone loss). Therefore, this project will lay the groundwork for the development of novel approaches to the treatment of periodontitis and other inflammatory diseases and identify therapeutic targets that should be readily translatable.